.alpha.-methylene-.gamma.-butyrolactone constitute an important group of natural products which possess wide-ranging biological activities, including antineoplastic, bactericidal, fungicidal, antibiotic and anthelminthic properties (Hoffmann et al., Angew. Chem. Int. Ed. Engl., 1985, 24, 94). The present invention relates to the synthesis and measurement of novel antineoplastic .alpha.-methylene-.gamma.-butyrolactones to be used in cancer therapy.
A number of sesquiterpenes bearing .alpha.-methylene-.gamma.-butyrolactone functionality such as helenaliry, and elephantopin have exhibited significant antitumor activities(Lee et al., J. Med. Chem., 1972, 15, 609). It was soon characterized that the structural requirement for the cytotoxicity is O.dbd.C--C.dbd.CH.sub.2 moiety which acts as an alkylating agent by a Michael-type reaction with biological cellular nucleophiles or sulphydryl-containing enzymes, leading to the breakage of DNA/RNA or the inhibition of enzyme activities(Kupchan et al., Science, 1970, 168, 376). Other clinically useful alkylating drugs against human malignancy are nitrogen mustards: uracil mustard, chloroambucil and cyclophosphamide. Their utilization is, however, limited by the poor selectivity and the serious side effects such as bone marrow toxicity. The individual drugs also produce distinctive toxic effects on the intestine, kidneys, heart and other organs. Therefore, efforts have been made wordwide to discover more active and less toxic antineoplastic agents. Certain .alpha.-methylene-.gamma.-butyrolactones had been prepared and screened (Lee et al., J. Med. Chem., 1977, 20,911; Heindel et al., J. Pharm. Sci., 1981, 70, 84; Sanyal et al., J. Med. Chem., 1986, 29, 595) . Recently, we described the synthesis and cytotoxicity of certain uracil .alpha.-methylene-.gamma.-butyrolactones and uncovered that an aryl substituent at 5-position of the .alpha.-methylene-.gamma.-butyrolactone ring enhanced the antitumor potency (Chin. Pharm. J. 1991, 43, 447; Kaohsiung J. Med. Sci., 1993, 9, 707). The present invention describes the preparation of certain novel .alpha.-methylene-.gamma.-butyrolactones as antineoplastic agents. All compounds were evaluated in vitro against a total of 56 human tumor cell lines derived from nine cancer types.